CCK-8-evoked cationic currents in substantia nigra dopaminergic neurons are mediated by InsP3-induced Ca2+ release.

Our recent study demonstrated that by activating CCK-A receptors, CCK-8 excites substantia nigra (SN) dopaminergic (DA) neurons via increasing a non-selective cationic conductance. In the present study, we further studied the molecular mechanism by which CCK-8 induces cationic currents in SN DA neurons. CCK-8-evoked inward currents were inhibited by the intracellular perfusion of GDP-beta-S (1 mM). In DA neurons internally perfused with GTP-gamma-S (0.5 mM), the inward currents produced by CCK-8 became irreversible. Pretreating DA neurons with 500 ng/ml pertussis toxin (PTX) did not significantly affect the ability of CCK-8 to induce cationic currents. Intracellular application of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (InsP3) receptor antagonist, and buffering intracellular calcium with the Ca(2+)-chelator BAPTA (10 mM) suppressed CCK-8-evoked cationic currents. Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), failed to prevent CCK-8 from generating cationic currents. It is concluded that PTX-insensitive G-proteins mediate CCK-8-induced enhancement of cationic conductance of SN DA neurons. The coupling mechanism via G-proteins is likely to involve the generation of InsP3, and subsequent InsP3-evoked Ca2+ release from the intracellular store results in activating the non-selective cationic conductance.